Predicting outcome of one-step total hysteroscopic resection of sessile submucous myoma

STUDY OBJECTIVE: To analyze variables for successful 1-step hysteroscopic myomectomies of sessile submucous myomas. DESIGN: Retrospective case-control study. (Canadian Task Force classification II-2). SETTING: Single operator's practice in a university hospital and its related hospitals. PATIENTS: Twenty-eight patients with sessile submucous myomas and menorrhagia, infertility, or both. INTERVENTIONS: Our strategy for hysteroscopic myomectomy is as follows. First, we scraped and/or vaporized intrauterine dome of myoma until top of myoma was even with level of wall of cavity. Next, the remnant intramural node was squeezed by uterine contractions induced by prostaglandin F2alpha injection. Finally, the newly raised myoma dome was sectioned or vaporized electrosurgically only within the space of the intrauterine cavity and/or was separated mechanically from healthy myometrium without electrosurgery. MEASUREMENTS AND MAIN RESULTS: Submucous myomas in 16 (57.1%) patients were completely removed after 1 surgery. By logistic regression analysis, thickness of outer myometrial layer of myoma node (OR 3.06, p = .02), myoma size (OR 0.86, p = .04), and intramural extension degree (OR 0.91, p = .03) were significantly associated with outcome of complete resection. CONCLUSION: Thickness of outer myometrial layer of myoma node, myoma size, and intramural extension degree predicted outcome of 1-step hysteroscopic myomectomy. The chance of performing successful surgery increased with increased thickness of outer myometrial layer of myoma, and decreased with larger myomas and greater degrees of intramural extension.     

Number of aberrant crypt foci in the rectum is a useful surrogate marker of colorectal adenoma recurrence

Aim: Endoscopic screening and removal of colorectal adenomas can reduce the incidence of colorectal cancer. However, given the possibility of adenoma recurrence, surveillance colonoscopy is currently recommended after the initial screening and removal of colorectal adenomas. Aberrant crypt foci (ACF) have been shown to serve as a reliable surrogate marker of colorectal carcinogenesis. In this study, the relationship between the number of ACF at the initial endoscopic polypectomy and the likelihood of colorectal adenoma recurrence after polypectomy were investigated. Methods: High‐magnification chromoscopic colonoscopy was performed in 82 subjects who underwent endoscopic polypectomy to identify ACF in the lower rectum. Surveillance colonoscopy was then performed 3 years after the baseline polypectomy at Yokohama City University Hospital. Results: The number of ACF was greater in patients who showed adenoma recurrence (7.88 ± 6.35) than in those who did not (2.19 ± 2.95) (P < 0.001). Receiver–operating curve analysis showed that the number of ACF was a highly specific predictor of the risk of adenoma recurrence. Conclusions: This is the first study conducted to investigate the relationship between the number of ACF after endoscopic polypectomy and the likelihood of recurrence of colorectal adenomas. These results suggest that the number of ACF is a useful predictor of the likelihood of colorectal adenoma recurrence.     

Genotypic and Phenotypic Analyses of Hepatitis C Virus from Patients Treated with JTK-853 in a Three-Day Monotherapy

JTK-853, a palm site-binding NS5B nonnucleoside polymerase inhibitor, shows antiviral activity in vitro and in hepatitis C virus (HCV)-infected patients. Here, we report the results of genotypic and phenotypic analyses of resistant variants in 24 HCV genotype 1-infected patients who received JTK-853 (800, 1,200, or 1,600 mg twice daily or 1,200 mg three times daily) in a 3-day monotherapy. Viral resistance in NS5B was investigated using HCV RNA isolated from serum specimens from the patients. At the end of treatment (EOT) with JTK-853, the amino acid substitutions M414T (methionine [M] in position 414 at baseline was replaced with threonine [T] at EOT), C445R (cysteine [C] in position 445 at baseline was replaced with arginine [R] at EOT), Y448C/H (tyrosine [Y] in position 448 at baseline was replaced with cysteine [C] or histidine [H] at EOT), and L466F (leucine [L] in position 466 at baseline was replaced with phenylalanine [F] at EOT), which are known to be typical resistant variants of nonnucleoside polymerase inhibitors, were observed in a clonal sequencing analysis. These substitutions were also selected by a treatment with JTK-853 in vitro, and the 50% effective concentration of JTK-853 in the M414T-, C445F-, Y448H-, and L466V-harboring replicons attenuated the susceptibility by 44-, 5-, 6-, and 21-fold, respectively, compared with that in the wild-type replicon (Con1). These findings suggest that amino acid substitutions of M414T, C445R, Y448C/H, and L466F are thought to be viral resistance mutations in HCV-infected patients receiving JTK-853 in a 3-day monotherapy.     

Jak3 negatively regulates dendritic-cell cytokine production and survival

Cytokines are critical in regulating the development and function of diverse cells. Janus kinase 3 (Jak3) is a tyrosine kinase expressed in hematopoietic cells that associates with the common gamma chain (gammac) and is required for signaling for a family of cytokines including interleukin-2 (IL-2), IL-4, IL-7, IL-9, IL-15, and IL-21; deficiency of either Jak3 or gammac results in severe combined immunodeficiency (SCID). While Jak3 is essential for lymphoid-cell development, the potential roles for Jak3 in regulating dendritic cells (DCs) were unclear. Herein, we show that although CD8+CD11c+ splenic DCs are absent in Jak3-/- mice, bone marrow-derived DCs developed normally in vitro from Jak3-/- precursor cells. In fact, the survival of Jak3-/- DCs was enhanced, and they expressed lower levels of proapoptotic proteins. Jak3-/- DCs exhibited normal antigen uptake and up-regulation of costimulatory molecules. However, Jak3-/- DCs produced more IL-12 and IL-10 in response to Toll-like receptor ligands, which correlated with enhanced T helper 1 (Th1) differentiation in vivo. In summary, Jak3 is not essential for DC development but unexpectedly appears to be an important negative regulator. These results may be relevant clinically for patients with SCID who have undergone hematopoietic stem cell transplantation and for patients who might be treated with a Jak3 inhibitor.     

Maternal GABAergic and GnRH/corazonin pathway modulates egg diapause phenotype of the silkworm Bombyx mori

Diapause represents a major developmental switch in insects and is a seasonal adaptation that evolved as a specific subtype of dormancy in most insect species to ensure survival under unfavorable environmental conditions and synchronize populations. However, the hierarchical relationship of the molecular mechanisms involved in the perception of environmental signals to integration in morphological, physiological, behavioral, and reproductive responses remains unclear. In the bivoltine strain of the silkworm Bombyx mori, embryonic diapause is induced transgenerationally as a maternal effect. Progeny diapause is determined by the environmental temperature during embryonic development of the mother. Here, we show that the hierarchical pathway consists of a γ-aminobutyric acid (GABA)ergic and corazonin signaling system modulating progeny diapause induction via diapause hormone release, which may be finely tuned by the temperature-dependent expression of plasma membrane GABA transporter. Furthermore, this signaling pathway possesses similar features to the gonadotropin-releasing hormone (GnRH) signaling system for seasonal reproductive plasticity in vertebrates.

To ensure survival under unfavorable environmental conditions and synchronize populations, most insect species enter diapause, which is a seasonal adaptation that evolved as a specific subtype of dormancy (1, 2). Diapause is not a passive response to changing conditions but rather an actively induced state that precedes adverse natural situations. Therefore, this diapause phenotype is accompanied by changes in energy metabolism or storage to improve cold/stress tolerance in later life stages, or progeny via reproductive switch (3). Although it has been generally suggested that brain/neuroendocrine systems are associated with this seasonal reproductive plasticity in both vertebrates and invertebrates (3, 4), the hierarchical relationship of the molecular mechanisms involved in the perception of environmental signals to integration into morphological, physiological, behavioral, and reproductive responses, known as the diapause syndrome, remains unclear (3).The silkworm Bombyx mori is a typical insect that arrests normal development during early embryogenesis, which is accompanied by metabolic changes in diapause (5, 6). The development of diapause-destined embryos is arrested during the G2 cell cycle stage immediately after the formation of the cephalic lobe and telson and sequential segmentation of the mesoderm (7). The bivoltine strain of B. mori has two generations per year, and progeny diapause is transgenerationally induced as a maternal effect and is determined by the environmental temperature, photoperiod, and nutrient conditions during embryonic and larval development of the mother (5, 6). The temperature signal during the mother’s embryonic development predominantly affects diapause determination, even if silkworms of the bivoltine Kosetsu strain are exposed to all cases of photoperiods during embryonic and larval development. In the Kosetsu strain, when eggs are incubated at 25 °C under continuous darkness, the resultant female moths (25DD) lay diapause eggs in almost all cases. In contrast, incubation of eggs at 15 °C in dark condition results in moths (15DD) that lay nondiapause eggs in almost all cases (6).Embryonic diapause is induced by the diapause hormone (DH) signaling pathway, which consists of highly sensitive and specific interactions between a neuropeptide, DH, and DH receptor (DHR) (6, 8). DH is exclusively synthesized in seven pairs of neurosecretory cells (DH-PBAN–producing neurosecretory cells [DHPCs]) located within the subesophageal ganglion (SG) in the mother’s generation (6). DH is released into the hemolymph during pupal–adult development and acts on the DHR, which belongs to the G protein-coupled receptors (GPCRs) (9). DH levels in the hemolymph are higher in the 25DD than 15DD pupae in the middle of pupal–adult development when the developing ovaries are sensitive to DH (6). Furthermore, the embryonic Bombyx TRPA1 ortholog (BmTRPA1) acts as a thermosensitive channel that is activated at temperatures above ∼21 °C and affects diapause induction through DH release (10). However, there remain questions about the thermal information that is received by BmTRPA1 and linked to DH signaling to induce diapause.From the 1950s, it has been suggested that the DH release was controlled by signals derived from certain region(s) in the brain based on surgical experiments, such as midsagittal bisection or transection (11–13). Especially, the operation in nondiapause producers changed them to diapause producers while transection of the protocerebrum had no effect on the diapause producers. These surgical results suggested the involvement of the protocerebrum in the inhibitory control of DH secretion (12, 14). Furthermore, the accumulation of the ovarian 3-hydroxykynurenine (3-OHK) pigment that accompanies the diapause syndrome was affected by injection with γ-aminobutyric acid (GABA) and the plant alkaloid picrotoxin (PTX), which is a widely used ionotropic GABA and glycine receptor antagonist (15, 16), and the selective ionotropic GABA receptor (GABAR) antagonist bicuculline. This suggests that a GABAergic neurotransmission via ionotropic GABAR is involved in DH secretion, which may be active in nondiapause producers but inactive in diapause producers throughout the pupal–adult development (14, 17). In general, ionotropic GABAR is composed of homo- or hetero-pentameric subunits. All known GABAR subunits display a similar structural scheme, with a large N-terminal extracellular domain involved in the formation of a ligand-binding pocket and a pore domain made of four transmembrane alpha-helices (TM1–TM4) (16, 18). Four homologous sequences of the ionotropic GABAR subunit genes were identified as RDL, LCCH3, GRD, and a GRD-like sequence named 8916 in various insects (19). However, the in vivo physiological roles of both signals derived from the brain and the GABAergic pathway in diapause induction have not been previously investigated.Corazonin (Crz) is an undecapeptide neurohormone sharing a highly conserved amino acid (a.a.) sequence across insect lineages and is involved in different physiological functions, such as heart contraction (20), stress response (21, 22), various metabolic activities (23–25), female fecundity (26), melanization of locust cuticles (27), regulation of ecdysis (28, 29), and control of caste identity (30). Moreover, Crz belongs to the gonadotropin-releasing hormone (GnRH) superfamily alongside adipokinetic hormone (AKH) and AKH/Crz-related peptide (ACP). Duplicates of an ancestral GnRH/Crz signaling system occurred in a common ancestor of protostomes and deuterostomes through coevolution of the ligand receptor (31, 32).Herein, we demonstrated that the hierarchical pathway consists of a GABAergic and Crz signaling system modulating progeny diapause induction by acting on DH release. We propose that the PTX-sensitive GABAergic signal may act to chronically suppress Crz release in dorsolateral Crz neurons (under nondiapause conditions) and that diapause conditions (or PTX injection) inhibits GABAergic signaling, resulting in accelerated Crz release, which in turn induces DH release. GABA signaling may be finely tuned by the temperature-dependent expression of the plasma membrane GABA transporter (GAT), which differs between the 25DD and 15DD conditions. Furthermore, this signaling pathway possesses similar features to the GnRH signaling system with respect to seasonal reproductive plasticity in vertebrates.     

Circadian dynamics of heart rate and physical activity in patients with heart failure

The present study was designed to develop a method to continuously measure Holter electrocardiogram (ECG) and physical activity in terms of metabolic costs to examine circadian dynamics of RR intervals and physical activity in patients with heart failure. A total of 7 healthy subjects and 3 heart failure patients performed cardiopulmonary exercise test using four-stage graded treadmill walking at 0% grade to examine whether the acceleration signals in the vertical direction could reflect actual body energy expenditure during physical activity. Then, using this new method, 24-hr monitorings of ECG and physical activity were performed in 24 inpatients with heart failure while they were allowed to walk around freely. Our results showed the integral of rectified acceleration signals was closely correlated with actual metabolic cost in all subjects. Instantaneous changes in heart rate were quite concordant with physical activity. As compared with the asymptomatic patients (n = 12), the symptomatic patients (n = 12) had lower energy expenditure during 8-hr daytime periods but higher mean heart rate. Furthermore, a more prominent ultradian rhythm of circadian changes in heart rate and physical activity was found in 50% of all subjects studied. The simultaneous analysis of Holter ECG and physical activity as the same time series revealed that in patients with heart failure, sympathovagal balance shifted toward sympathotonic conditions and their physical activity could become subject to intrinsic ultradian dynamics of body's homeostasis.     

Utility of a simplified ultrasonography scoring system among patients with rheumatoid arthritis: A multicenter cohort study

We aimed to evaluate the utility of a simplified ultrasonography (US) scoring system, which is desired in daily clinical practice, among patients with rheumatoid arthritis (RA) receiving biological/targeted synthetic disease-modifying antirheumatic drugs (DMARDs).A total of 289 Japanese patients with RA who were started on tumor necrosis factor inhibitors, abatacept, tocilizumab, or Janus kinase inhibitors between June 2013 and April 2019 at one of the 15 participating rheumatology centers were reviewed. We performed US assessment of articular synovia over 22 joints among bilateral wrist and finger joints, and the 22-joint (22j)-GS and 22-joint (22j)-PD scores were evaluated as an indicator of US activity using the sum of the GS and PD scores, respectively.The top 6 most affected joints included the bilateral wrist and second/third metacarpophalangeal joints. Therefore, 6-joint (6j)-GS and -PD scores were defined as the sum of the GS and PD scores from the 6 synovial sites over the aforementioned 6 joints, respectively. Although the 22j- or 6j-US scores were significantly correlated with DAS28-ESR or -CRP scores, the correlations were weak. Conversely, 6j-US scores were significantly and strongly correlated with 22j-US scores not only at baseline but also after therapy initiation.Using a multicenter cohort data, our results indicated that a simplified US scoring system could be adequately tolerated during any disease course among patients with RA receiving biological/targeted synthetic DMARDs.     

A case of pseudoxanthoma elasticum associated with sick sinus syndrome

Typical angioid streaks were found on routine ophthalmologic examination in a 42-year-old female with yellowish, coalescing papules on her neck without any symptoms. Biopsy of the cutaneous lesion showed degeneration and fragmentation of the elastic fibers and many basophilic-stained calcifications in mid-dermis, which are consistent with pseudoxanthoma elasticum. Twenty-four-hour Holter electrocardiography (ECG) showed sinus arrest for 2.5 seconds, and an electrophysiological study revealed sinus nodal dysfunction (sick sinus syndrome), whereas all of the coronary arteries were intact, despite a treadmill stress ECG test showing significant ST depressions. The association of pseudoxanthoma elasticum and sick sinus syndrome is very rare. One possible explanation for this association here is that the degeneration of elastic fiber in endomysium of the sino-atrial node may have affected heart conduction systems, resulting in sick sinus syndrome.Part of this work was presented at the 76th Japanese Circulation Society Kyushu Meeting, Japan, June 18, 1994     

Anti-PM/Scl Antibody-positive Systemic Sclerosis Complicated by Multiple Organ Involvement

A 40-year-old Japanese woman developed malignant-phase hypertension complicated by thrombotic microangiopathy, progressing to end-stage renal disease. Five years later, she was diagnosed with pulmonary arterial hypertension and interstitial pneumonia. Despite a lack of overt skin sclerosis, nucleolar staining in our indirect immunofluorescence analysis and nailfold capillaroscopy facilitated the diagnosis of anti-PM/Scl antibody-positive systemic sclerosis. We observed the persistent presence of anti-PM/Scl antibodies throughout the clinical course, suggesting that her kidney disease was scleroderma renal crisis. Anti-PM/Scl antibodies can be associated with multiple organ diseases. Careful attention to a patient''s antinuclear antibody pattern and dermatological findings may help clarify the etiology of undiagnosed diseases.     

Laparoscopy-assisted spleen-preserving distal pancreatectomy with conservation of the splenic artery and vein

Herein, we report the successful performance of a laparoscopy-assisted spleen-preserving distal pancreatectomy with conservation of the splenic artery and vein for a patient with pancreatic cystadenoma, as a minimally invasive procedure with the preservation of function. The laparoscopy-assisted distal pancreatectomy procedure involved detaching the spleen and the distal pancreas from the retroperitoneum by a hand-assisted procedure, removing them from the peritoneal cavity through a small incision, and detaching the distal pancreas by ligating and transecting the short gastric artery and vein and the branches of the splenic artery and vein, while the spleen and main splenic artery and vein were preserved under direct view. The pancreatic parenchyma was transected with a stapling device (TL-30), and continuous suturing was added to the resected margin. The patient’s postoperative course was uneventful; the patient started to eat and walk on postoperative day 2 and was discharged on day 8. It is considered that the combination of hand-assisted and laparoscopy-assisted distal pancreatectomy, with conservation of the splenic artery and vein, is a minimally invasive and clinically useful technique for treating tumors of cystic disease of the pancreas with low-grade malignant potential, or benign solitary neuroendocrine tumors.